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`VEGF Trap-Eye for the
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`age-related macular
`degeneration
`JA Dixon, SCN Oiiver, JL Olson &
`N Mandava
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`Drug Evaluation
`W
`
`Expert
`Opinion
`
`VEGF Trap-Eye for the treatment
`, of neovascular age-related
`macular degeneration
`
`James A Dixon, Scott CN Oliveri, Jefirey L Olson 86 Naresh Mandava
`University ofColamdo Denver, Rocky Mountain Liam Eye [IPSZIUIIG Department ofOp/fl/m/mv/ogy,
`1675 Nari/J Aurora Court. PO Box 6510. Mail Stop E731, Aurora, CO 80045—2500, USA
`
`Background: Age-related macular degeneration (AMD) affects > 14 million
`individuals worldwide. Although 90% of patients with AMD have the dry
`form, neovascular AMD accounts for the vast majority of patients who
`develop legal blindness. Until recently, few treatment options existed for
`treatment of neovascular AMD. The advent of anti—VEGF therapy has sig—
`nificantly improved the safe and effective treatment of neovascular AMD.
`in addition to two anti-VEGF drugs currently in widespread use, ranibizumab
`and bevacizumab, a number of medications that interrupt angiogenesis are
`currently under investigation. One promising new drug is aflibercept (VEGF
`Trap-Eye), a fusion protein that blocks all isoforms of VEGF—A and placental
`growth factors-1 and -Z. Objective: To review the current literature and clini-
`cal trial data regarding VEGF Trap-Eye for the treatment of neovascular
`AMD. Methods: Literature review. Results/conclusion: VEGF Trap~Eye is a
`novel anti-VEGF therapy, with Phase I and II trial data indicating safety, toler-
`ability and efficacy for the treatment of neovascular AMD. Two Phase Ill clini-
`cal trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are
`currently continuing and will provide vital insight into the clinical applicability
`of this drug.
`
`Keywords: ailibercept, AMD‘ nngiogenesis. neovascularization. VEGF, VEGF inhibition. VEGF Trap
`
`Expert Opin. I'm/6mg. Drugs (2009) 18(1 011573-1580
`
`1. Introduction
`
`M A
`
`ge—related macular degeneration (AMD) afiects > 1.75 million individuals in the
`US and it is estimated that by 2020 this number will increase to almost 3 million [11.
`Worldwide, AMD is estimated to affect 14 million people (21. While the vast major—
`ity of patients suffering from AMD have the dry form, ~ 80 ~ 90% of patients who
`develop severe vision loss have the neovascular or ‘wet’ form of the disease 13}. Until
`recently, healthcare professionals had few options when it came to treating neovascular
`AMD. For many years, subfoveal choroidal neovascularization (CNV) was treated
`with argon laser therapy according to guidelines from the Macular Photocoagulation
`Study [4-12]. This treatment, in the setting of subfoveal disease, was unsatisfactory for
`a number of reasons, including the limited benefits in visual stabilization and the
`high risk of inducing central vision deficits 113]. Treatment outcomes improved with
`the introduction of photodynamic therapy (PDT) which utilized a photosensitizing
`dye (verteporfin) to selectively target CNV. While more efficacious than previous
`treatments, patients receiving PDT Failed to recover vision and continued to experi—
`ence a decline in visual acuity [141 and the treatment was of questionable cost
`effectiveness [15l-
`largely
`inhibit VEGF has
`The more recent development of agents that
`supplanted these previous treatments. The pathogenesis of CNV in the setting of
`
`1.
`
`Introduction
`
`2. Background
`3- Conclusion
`4.
`Expert opinion
`
`info rma
`healthcare
`
`l
`
`0,1 517/1 3543780903201684 o 2009 Informa UK Ltd lSSN 1354-3784
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`VEGF Trap-Eye
`
`AMD is complex; however, there is overwhelming evidence
`that VEGF is a predominant mediator in its genesis. VEGF
`receptors are expressed by a number of important cell types
`in the eye,
`including vascular endothelial cells, choroidal
`fibroblasts, retinal pigment epithelial cells and inflammatory
`cells attracted by hypoxia [16—19]. Higher levels of VEGF
`expression have been demonstrated in animal models [20,21]
`and human studies of eyes with AMD [1122—24] and antago—
`nism of VEGF in both settings have definitively demon—
`strated inhibition ofneovascularizan'on and vascular permeability.
`VEGF—A is the predominant member of the VEGF family
`targeted by drugs currently in widespread use; however,
`the
`group is also comprised of VEGF—B, VEGF—C, VEFG—D and
`placental growth factors-1 and -2.
`Systemic administration of bevacizumab is elfective against
`neovascular AMD; however, systemic complications limit its
`use [25]. Accordingly, all anti—VEGF agents for neovascular
`AMD are administered only by intravitreal injection. The two
`largest studies examining anti—VEGF therapy, the MARINA [26]
`and the ANCHOR [27,28] trials, were randomized, controlled,
`double—masked Phase III clinical trials that together evaluated
`monthly ranibizumab for the treatment of all types of neovas-
`cular AMD. In both trials, 94% of patients with neovascular
`AMD lost fewer than 15 letters of visual acuity at 12 and
`24 months when treated with ranibizumab. Surprisingly, as
`many as 40% of patients in the two trials improved by > 15
`letters from baseline at 2 years. Ranibizumab received the
`FDA approval for all
`types of neovascular AMD in 2006.
`Based on the results of these two landmark studies, anti-VEGF
`therapies for neovascular AMD have largely replaced previous
`treatment modalities.
`
`Macular Degeneration Treatment Trial (CATT) is a 2—year,
`multi-centered, randomized clinical
`trial comparing ranibi-
`zumab and bevacizumab for neovascular AMD. Enrollment
`began in February 2008. Despite the off-label status of beva-
`cizumab, it continues to be a popular treatment choice in the
`US because of the significantly reduced price of treatment
`($ 50 — 100 for bevacizumab versus $ 2000 for ranibizumab
`(2008 pricing)).
`the MARINA [26] and the
`As previously mentioned,
`ANCHOR [27,28] trials examined the efficacy of ranibizumab
`when administered monthly. The time and financial burden
`of monthly injections has led to the initiation of studies to
`examine the efficacy of alternative dosing schedules. In the
`PIER study [30], patients initially received monthly injections
`of ranibizumab for 3 months followed by quarterly injec-
`tions. Although patient visual acuities actually improved at
`3 months, during the quarterly dosing segment visual acuity
`returned to baseline. The PrONTO study [29] looked at as
`needed (p.r.n.) dosing of ranibizumab after three consecutive
`monthly doses. The need for further injections was made on
`the basis of recurrent CNV as evidenced by worsening
`vision, retinal thickening on ocular coherence tomography
`(OCT) or abnormalities on fluorescein angiogram (FA). At
`2 years of follow up, 78% of patients had maintained vision
`and vision had improved by > 3 lines in 43% of patients
`with an average of five injections a year. These later studies
`seem to indicate that quarterly closing is associated with
`poorer outcomes but it may be possible to extend the time
`between injections if the patient is frequently monitored.
`However, even with the fun dosing utilized in the PrONTO
`study, patients are still required to make monthly visits to the
`office with frequent and expensive testing.
`The development of new drugs for neovascular AMD has
`thus focused on both improving efficacy and extending
`duration of action. Most new compounds in development
`are targeted toward inhibition of various steps in the VEGF
`signaling pathway. There are a number of drugs in develop-
`ment that inhibit die downstream tyrosine kinase cascade
`activated by the binding of VEGF with its
`receptor
`(VEGFR). Vatalanib is an oral formulation that binds to all
`three VEGFRs and has recently completed Phase I/II study
`as adjuvant to PDT and ranibizumab [33]. Topical tyrosine
`kinase inhibitors currently undergoing Phase II clinical stud—
`ies include pazopanib [34] and TG100801 [55]. Another
`approach utilims siRNA to silence genes which express pro-
`teins involved in angiogenesis. Bevasiranib, an siRNA that
`targets VEGF-A mRNA, showed encouraging Phase I and II
`data, but the Phase III trial was halted in March 2009 for
`projected failure to meet the primary end point
`[36]. An
`extra antiangiogenic target being developed is pigment
`epithelium—derived factor (PEDF), a potent inhibitor of new
`vessel growth. AdGVPEDEIID uses an adenovector
`to
`deliver the PEDF gene to target cells, resulting in the local
`production of PEDF in the treated eye. AdGVPEDEIID
`has recently completed Phase I clinical trials [37]. Another
` 1574
`Expert Opin. Investig. Drugs (2009) 18(10)
`
`2. Background
`
`2.1 Overview of the market (unmet needs,
`competitor compounds/in clinical development)
`By far the most commonly used anti—VEGF drugs currently
`in use for neovascular AMD are ranibizumab and bevaci—
`zumab. Pegapmnib was the first anti—VEGF drug approved
`by the FDA for the treatment of AMD; however, it proved
`less efficacious than current treatments [13] (possibly due to
`its selective binding of VEGF-165) and is no longer widely
`used in most countries. Ranibizumab is the only drug in
`widespread use currently approved by the FDA for treat-
`ment of neovascular AMD and is by far the most extensively
`studied [26,27,29,30]. It is a recombinant monoclonal antibody
`fragment with a high binding aflinity for all
`isotypes of
`VEGF—A. Bevacizumab, currently being used off—label for
`the treatment of AMD in the US,
`is a humanized whole
`antibody to VEGF—A used in oncology regimens that also
`binds all
`isotypes of VEGF—A. Although ranibizumab has
`been shown to have a higher affinity for VEGF-A, it is not
`clear if ranibizumab has superior efficacy to bevacizumab.
`Retrospective and small randomized studies have suggested
`similar efficacy profiles [31,32]. The Comparisons ofAge—Related
`
`Regeneron Exhibit 1030.005
`
`

`

`recently discovered alternative pathway for decreasing angio—
`genesis involves inhibition of nicotinic acetylcholine recep—
`tors. ATG3 (mecamylamine), a topical
`formulation that
`inhibits the nicotinic acetylcholine receptors, has shown
`promising results in animal and Phase I trials and is currently
`undergoing a Phase II study [25].
`
`2.2 Introduction to compound
`VEGF Trap-Eye is a novel anti—VEGF drug currently in
`commercial development for the treatment of neovascular
`AMD by Regeneron Pharmaceuticals, Inc. (Tarrytown, NY,
`USA) in the US and in collaboration with Bayer HealthCare
`(Leverkusen, Germany)
`in global markets. Structurally,
`VEGF Trap—Eye is a firsion protein of key binding domains
`of human VEGFR—l and —2 combined with a human IgG
`Fc fragment (Figure 1). Functionally, VEGF Trap—Eye acts as
`a receptor decoy with high aflinity for all VEGF isoforms,
`binding more tightly than their native receptors. Unlike
`anti-VEGF drugs currently in use, VEGF Tiap—Eye
`is
`designed to inhibit placental growth factors—1 and -2 in
`addition to all isoforms of VEGF-A.
`
`2.3 Chemistry
`VEGF Trap—Eye and aflibercept (the oncology product) have
`the same molecular structure, but there are substantial dif-
`ferences between the preparation of the purified drug prod-
`uct and their formulations. Both aflibercept and VEGF
`Trap—Eye are manufactured in bioreactors from industry
`standard Chinese hamster ovary cells that overexpress the
`fusion protein. However, VEGF Trap—Eye undergoes firrther
`purification steps during manufacturing to minimize risk of
`irritation to the eye. VEGF Trap—Eye is also formulated with
`different buffers and at different concentrations (for buffers
`in common) suitable for the comfortable, non—irritating,
`direct injection into the eye.
`
`2.4 Pharmacodynamics
`The aflibercept dose that is administered in oncology settings
`is either 4 mg/kg every 2 weeks or 6 mg/kg every 3 weeks,
`which corresponds to 2 mg/(kg week) with either schedule.
`The highest intravitreal dose being used in pivotal trials for
`VEGF Trap-Eye is 2 mg/month, which corresponds to at
`least a 280-fold lower potential systemic exposure than in the
`oncology setting. Early trials with aflibercept administered
`intravenously for AMD indicated that doses of 0.3 mg/kg
`(21 mg total) were inadequate to fully capture systemic
`VEGF. Thus, the low intravitreal dose of 2 mg allows for
`extended blocking of VEGF in the eye, but would be pre-
`dicted to give negligible systemic activity as it will be rapidly
`bound to VEGF and inactivated.
`
`2.5 Pharmacokinetics and metabolism
`Aflibercept is cleared from circulation through two pathways:
`by binding to VEGF to form an inactive VEGF—aflibercept
`complex and by Fc—receptor or pinocytotic mediated pathways
`
`Dixon, Oliver, Olson & Mandava
`
`that end in proteolysis, which are presumed to be similar to
`pathways that metabolize antibodies. At very high doses, free
`aflibercept has a terminal half-life of ~ 17 days in the circu-
`lation. The half—life of human intravitreal doses is unknown.
`Intravitreal primate doses of ranibizumab have a half—life of
`~ 3 days [38]. At low blood levels, clearance of free afliber—
`cept is rapid as a result of binding to VEGF with picomolar
`affinity [39].
`
`2.6 Clinical efficacy
`2.6.1 Phase!
`
`A Phase I, randomized, double—blind, placebo—controlled trial
`of intravenous aflibercept (oncology formulation) was com—
`pleted in 25 patients with AMD. Although systemic afliber—
`cept did demonstrate a dose—dependent decrease in retinal
`thickness,
`the study was halted due to concerns of dose—
`dependent toxicity when one patient developed hypertension
`and another proteinuria [40].
`The safety, tolerability and biological activity of intravitreal
`VEGF Trap—Eye in treatment of neovascular AMD was cval~
`uated in the two—part Clinical Evaluation ofAnti—angiogenesis
`in the Retina—1 (CLEAR—IT—l) study [41]. The first part was
`a sequential cohort dose-escalation study in which 21 patients
`were monitored for safety, changes in foveal
`thickness on
`OCT, best corrected visual acuity (BCVA) and lesion size on
`FA for 6 weeks. No adverse systemic or ocular events were
`noted and visual acuity remained stable or improved 2 3
`lines in 95% of patients with a mean increase in BCVA
`of 4.6 letters at 6 weeks [42]. Patients showed substantially
`decreased foveal thickness [41].
`In the second part, 30 patients received a single intravitreal
`injection of either 0.5 or 4 mg of VEGF Trap—Eye and were
`followed for 8 weeks. All patients were evaluated for their
`rates of retreatment, changes in BCVA, foveal thickness as
`well as change in total lesion size and area of CNV. Patients
`had ETDRS (Early Treatment of Diabetic Retinopathy
`Study) BCVA ranging from 20/40 to 20/320 with any angio—
`graphic subtype of CNV at baseline. No serious adverse
`events or ocular inflammation was identified during the
`study. At 8 weeks, the mean decrease in retinal thickness in
`the low dose group was 63.7 um compared to 175 pm for
`the high dose group. Of the first 24 patients to complete the
`study, 11 out of 12 patients in the 0.5 mg dose group
`required retreatrnent in a median of 64 days, compared with
`4 out of 12 in the 4 mg dose group who required retreatment
`in a median of 69 days [43].
`VEGF Trap-Eye has also undergone a small open-label
`safety study for the treatment of diabetic macular edema
`(DME) [44]. The drug was administered as a single 4 mg
`intravitreal injection to five patients with longstanding dia—
`betes and several previous treatments for DME. The single
`injection resulted in a median decrease of central macular
`thickness measured by OCT of 79 pm. BCVA increased by
`9 letters at 4 weeks and regressed to a 3 letter improvement
`at 6 weeks.
`
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`retinal thickness versus baseline of 143 um (p < 0.0001) in the
`2.0 mg group and 125 um (p < 0.0001) in the 0.5 mg group
`at 52 weeks as measured by OCT [45].
`Patients in the three quarterly dosing groups also showed
`mean improvements in BCVA and retinal thickness; how-
`ever, they were generally not as profound as the monthly
`injection group [45].
`
`2.6.3 Phase III
`
`A two part Phase III trial of VEGF 'Il'ap~Eye was initiated in
`August of 2007. The first part, VIEW 1
`(VEGF Trap:
`Investigation of Efficacy and safety in Wet age—related macular
`degeneration) [46] will enroll ~ 1200 patients with neovascu—
`lat AMD in the US and Canada. This non—inferiority study
`will evaluate the safety and efficacy of intravitreal VEGF
`Trap—Eye at doses of 0.5 and 2.0 mg administered at 4-week
`dosing intervals and 2.0 mg at an 8 week dosing interval
`(following three monthly doses), compared with 0.5 mg of
`ranibizumab administered every 4 weeks. After the first year
`of the study, patients will enter a second year of p.r.n. dosing
`evaluation. The VIEW 2 [47] study has a similar study design
`and is currently enrolling patients in Europe, Asia Pacific,
`Japan and Latin America. In both trials, the primary out-
`come will be the proportion of patients who maintain vision
`at week 52 (defined as a loss of < 15 ETDRS letters).
`
`2.7 Safety and tolerability
`Based on Phase II study data, VEGF Trap-Eye seems to be
`generally well tolerated with no serious drug-related adverse
`events. In the 157 patients enrolled in CLEAR—IT 2 trial,
`there was one reported case of culture—negative endophthal—
`mitis not deemed to be related to the study drug. There
`were also two deaths (one from pre-existing pulmonary
`hypertension and one from pancreatic carcinoma) and one
`arterial thromboembolic event (in a patient with a history of
`previous stroke) that occurred during the study period, but
`no serious systemic adverse events were deemed related to
`VEGF Trap-Eye administration. The most common adverse
`events reported in the study included conjunctival hemor—
`rhage
`(38.2%),
`transient
`increased intraocular pressure
`(18.5%),
`refraction disorder (15.9%),
`retinal hemorrhage
`(14.6%),
`subjective visual acuity loss
`(13.4%), vitreous
`detachment (11.5%) and eye pain (9.6%) [45].
`
`3. Conclusion
`
`VEGF Trap-Eye
`
`VEGFR1
`
`VEGFRZ
`
`VEGF
`Trap
`
`Fc
`
`Kn
`
`10 — so pM
`VEGFR1
`VEGFRZ 100 — 300 pM
`VEGF Trap Eye ~ 0.5 pM
`
`
`
`o C q o o a o
`
`
`
`
`
`Figure 1. Schematic diagram of VEGF Trap-Eye, a fusion
`protein of binding domains of VEGF receptors-1 and -2
`attached to the Fc fragment of human IgG.
`
`2.6.2 Phase II
`
`randomized,
`[45] was a prospective,
`CLEAR-IT~2 trial
`multi~center, controlled dose— and interval—ranging Phase II
`trial in which 157 patients were randomized to five dose
`groups and treated with VEGF Trap—Eye in one eye. The
`mean age of the group was 78.2 years and all angiographic
`subtypes of CNV were represented at baseline. The mean
`ETDRS BCVA in letters at baseline was 56. Two groups
`received monthly doses of either 0.5 or 2.0 mg for 12 weeks
`(at weeks 0, 4, 8 and 12) and three groups received quar—
`terly doses of either 0.5, 2.0 or 4.0 mg for 12 weeks
`(at weeks 0 and 12). Following this fixed dosing period,
`patients were treated with the same dose of VEGF Trap—Eye
`on a p.r.n. basis. Criteria for re—dosing included an incrwse in
`central retinal thickness of 2 100 pm by OCT, a loss of 2 5
`ETDRS letters in conjunction with recurrent fluid by OCT,
`persistent fluid as indicated by OCT, new onset classic neo-
`vascularization, new or persistent leak on FA or new macular
`subretinal hemorrhage.
`Patients initially treated with 2.0 or 0.5 mg of VEGF Trap-
`Eye monthly achieved mean improvements of 9.0 (p < 0.0001)
`and 5.4 (p < 0.085) ETDRS letters with 29 and 19% gaining,
`respectively, 2 15 ETDRS letters at 52 weeks. During the
`p.r.n. dosing period, patients initially closed on a 2.0 mg
`monthly schedule received an average of 1.6 more injections
`and those initially dosed on a 0.5 mg monthly schedule
`received an average of 2.5 injections. The median time to first
`reinjection in all groups was 110 days and 19% of patients
`required no more injections at week 52. Patients in these two
`monthly dosing groups also displayed mean decreases in
`
`Anti-VEGF therapy has vastly improved the treatment of
`neovascular AMD in terms of both safety and efficacy The
`ANCHOR [26] and MARINA [27,28]
`trials have established
`ranibizumab as an effective therapy when dosed monthly. It
`has been shown to stabilize vision in 94% of patients and in
`almost 40% of patients vision will actually improve by 3 or
`more lines. However, the monthly dosing schedules used in
`these trials present a financial and time burden to patients
`and healthcare practitioners. The more recent PIER [so] and
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`trials have shown that ranibizumab is less
`PrONTO [29]
`effective when dosed quarterly, but it may be possible to
`extend the time between injections when patients are
`' followed closely with frequent examinations and ancillary
`testing. The most effective dosing regimen and monitoring
`program for anti—VEGF therapy has yet to be firmly estab—
`lished but new treatments are aimed at extending and
`improving on the efficacy of ranibizumab. VEGF Trap-Eye
`differs from established anti—VEGF therapies in its higher
`binding affinity for VEGF—A and its blockage of placental
`growth factors-1 and —2. Phase I data demonstrated accept-
`able safety and tolerability of VEGF Trap—Eye in the treat—
`ment of neovascular AMD. In Phase II study data, patients
`dosed in a similar fashion to the PrONTO trial demon-
`strated stabilization of their vision that was similar to previ—
`ous studies of ranibizumab at 1 year. Of the greatest interest,
`patients dosed at 2.0 mg during the initial monthly dosing
`period required 1.6 injections on average during the p.r.n.
`dosing phase. While this number is difficult to compare
`directly to the number of injections required during the
`p.r.n. phase of the PrONTO ranibizumab study, it is prom-
`ising. A direct comparison of the efficacy ofVEGF Trap—Eye
`versus ranibizumab will be possible with the completion of
`two Phase III trials, the VIEW-1 and -2 studies.
`
`encapsulated cell technology for sustained—release anti—VEGF
`therapy, no investigational drugs or devices have progressed
`yet to clinical trial enrollment.
`VEGF Trap—Eye represents the most promising anti-VEGF
`investigational drug that is currently in Phase III trial. VEGF
`Trap—Eye, a decoy VEGF receptor protein, binds all isoforms
`of free VEGF with high affinity, in addition to placental
`growth factor. In contrast to current anti—VEGF antibodies,
`which are rapidly cleared, the VEGF—VEGF Trap complex
`is relatively inert, and is degraded more slowly. Due to its
`high binding affinity and the ability to safely inject high
`doses into the eye, VEGF Trap—Eye may have longer dura-
`tion of effect in the eye. Two Phase III studies in wet AMD,
`VIEW 1 and VIEW 2, are currently under way and seek to
`compare monthly ranibizumab to monthly or bimonthly
`VEGF Trap—Eye.
`Data from the Phase II study with VEGF Trap—Eye were
`positive and the results from the non—inferiority Phase III
`trials will establish its efficacy versus ranibizumab. Its adop-
`tion into clinical practice will depend on efficacy at 4 and
`8 week intervals. If effective at 4 week intervals only, VEGF
`Trap—Eye will be adopted into clinical practice if it offers a
`competitive price advantage over ranibizumab. If effective at
`8 week intervals, VEGF Trap—Eye offers the opportunity to
`significantly r